Section

Bookeeping tables during data processing

ID before and after main file
Before After
1 1
2 2
3 3
4 4
5 5
6 6
7 7
8 8
9 9
10 10
11 11
12 12
13 13
14 14
15 15
16 16
17 17
18 18
19 19
20 20
21 21
22 22
23 23
24 24
25 25
26 26
27 27
28 28
29 29
30 30
31 31
32 32
33 33
34 34
35 35
36 36
37 37
38 38
39 39
40 40
41 41
42 42
43 43
44 44
45 45
46 46
47 47
48 48
49 49
50 50
51 51
62 62
63 63
64 64
65 65
66 66
67 67
68 68
69 69
70 70
71 71
72 72
73 73
74 74
75 75
76 76
77 77
78 78
79 79
80 80
81 81
82 82
83 83
84 84
85 85
86 86
87 87
88 88
89 89
90 90
91 91
92 92
93 93
94 94
95 95
96 96
97 97
98 98
99 99
100 100
101 101
102 102
103 103
104 104
105 105
106 106
AAL-01 AAL1
AAL-02 AAL2
AAL-03 AAL3
AAL-04 AAL4
AAL-05 AAL5
USC-52 USC52
USC-53 USC53
USC-54 USC54
USC-55 USC55
USC-56 USC56
USC-57 USC57
USC-59 USC59
USC-60 USC60
IDs in main file but not in VAFS
x
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
AAL1
AAL2
AAL3
AAL4
AAL5
USC52
USC53
USC54
USC55
USC56
USC57
USC59
USC60
ID before and after VAFS file
Before After
1 1
1 1
1 1
1 1
1 1
1 1
2 2
2 2
3 3
3 3
3 3
3 3
3 3
4 4
4 4
4 4
5 5
5 5
5 5
5 5
6 6
6 6
6 6
6 6
6 6
6 6
6 6
6 6
7 7
7 7
7 7
7 7
7 7
8 8
8 8
8 8
8 8
8 8
8 8
8 8
8 8
8 8
8 8
8 8
8 8
8 8
8 8
8 8
9 9
9 9
9 9
9 9
9 9
9 9
9 9
9 9
9 9
9 9
10 10
10 10
10 10
10 10
10 10
10 10
10 10
11 11
11 11
12 12
12 12
12 12
12 12
12 12
12 12
12 12
12 12
12 12
12 12
13 13
13 13
13 13
13 13
13 13
13 13
13 13
13 13
13 13
13 13
13 13
13 13
15 15
15 15
15 15
15 15
15 15
15 15
15 15
16 16
16 16
16 16
16 16
16 16
17 17
17 17
17 17
17 17
17 17
17 17
18 18
18 18
18 18
18 18
19 19
19 19
19 19
19 19
19 19
19 19
20 20
20 20
20 20
20 20
20 20
21 21
21 21
21 21
21 21
21 21
21 21
21 21
22 22
22 22
22 22
22 22
22 22
22 22
22 22
22 22
22 22
23 23
23 23
23 23
23 23
24 24
24 24
24 24
24 24
25 25
25 25
25 25
25 25
25 25
25 25
25 25
25 25
25 25
26 26
26 26
26 26
26 26
26 26
26 26
26 26
26 26
26 26
26 26
26 26
26 26
27 27
27 27
28 28
28 28
28 28
28 28
29 29
29 29
29 29
29 29
29 29
29 29
30 30
30 30
30 30
30 30
30 30
30 30
30 30
30 30
30 30
30 30
30 30
30 30
30 30
30 30
30 30
30 30
30 30
31 31
31 31
31 31
31 31
31 31
31 31
31 31
31 31
31 31
31 31
31 31
31 31
31 31
32 32
33 33
33 33
34 34
34 34
34 34
34 34
35 35
35 35
35 35
35 35
35 35
35 35
35 35
35 35
35 35
35 35
35 35
36 36
36 36
36 36
36 36
36 36
36 36
36 36
36 36
37 37
37 37
37 37
37 37
37 37
37 37
37 37
37 37
37 37
38 38
38 38
39 39
39 39
40 40
40 40
40 40
41 41
41 41
41 41
41 41
41 41
41 41
41 41
41 41
42 42
42 42
43 43
44 44
44 44
44 44
44 44
45 45
45 45
45 45
45 45
45 45
45 45
45 45
46 46
46 46
46 46
46 46
47 47
47 47
47 47
47 47
47 47
47 47
47 47
47 47
47 47
48 48
48 48
49 49
49 49
50 50
50 50
50 50
50 50
50 50
51 51
51 51
51 51
51 51
51 51
51 51
51 51
51 51
62 62
62 62
62 62
62 62
62 62
62 62
63 63
63 63
64 64
64 64
64 64
64 64
64 64
64 64
64 64
65 65
65 65
66 66
66 66
66 66
66 66
66 66
66 66
66 66
66 66
67 67
67 67
67 67
67 67
67 67
67 67
67 67
67 67
67 67
67 67
67 67
68 68
68 68
68 68
68 68
69 69
69 69
69 69
69 69
69 69
69 69
69 69
69 69
69 69
69 69
69 69
69 69
69 69
69 69
69 69
70 70
70 70
70 70
70 70
70 70
70 70
70 70
70 70
71 71
71 71
71 71
71 71
71 71
71 71
71 71
71 71
71 71
72 72
72 72
73 73
73 73
73 73
73 73
73 73
73 73
73 73
73 73
73 73
73 73
74 74
74 74
74 74
74 74
74 74
74 74
75 75
75 75
75 75
75 75
76 76
76 76
77 77
77 77
78 78
78 78
78 78
78 78
78 78
78 78
78 78
78 78
78 78
78 78
78 78
78 78
78 78
78 78
78 78
79 79
79 79
79 79
79 79
79 79
79 79
79 79
79 79
79 79
80 80
80 80
80 80
80 80
80 80
80 80
81 81
81 81
81 81
81 81
81 81
81 81
81 81
81 81
81 81
81 81
81 81
81 81
82 82
83 83
83 83
83 83
83 83
83 83
83 83
83 83
84 84
84 84
84 84
84 84
84 84
84 84
85 85
85 85
86 86
86 86
86 86
86 86
87 87
87 87
87 87
87 87
88 88
88 88
88 88
88 88
88 88
88 88
88 88
89 89
89 89
89 89
89 89
89 89
89 89
89 89
89 89
90 90
90 90
91 91
91 91
91 91
91 91
91 91
91 91
92 92
92 92
92 92
92 92
93 93
93 93
93 93
93 93
93 93
93 93
93 93
93 93
94 94
94 94
94 94
94 94
95 95
95 95
95 95
95 95
95 95
95 95
97 97
97 97
97 97
97 97
97 97
97 97
98 98
98 98
98 98
98 98
98 98
98 98
99 99
99 99
100 100
100 100
100 100
101 101
101 101
102 102
102 102
103 103
103 103
103 103
103 103
103 103
103 103
103 103
103 103
103 103
104 104
104 104
104 104
104 104
104 104
104 104
104 104
104 104
104 104
104 104
104 104
104 104
105 105
105 105
105 105
105 105
105 105
105 105
105 105
105 105
105 105
105 105
105 105
106 106
106 106
106 106
106 106
106 106
106 106
106 106
106 106
USC-52 USC52
USC-52 USC52
USC-52 USC52
USC-52 USC52
USC-52 USC52
USC-53 USC53
USC-53 USC53
USC-53 USC53
USC-53 USC53
USC-53 USC53
USC-53 USC53
USC-53 USC53
USC-53 USC53
USC-53 USC53
USC-53 USC53
USC-53 USC53
USC-53 USC53
USC-53 USC53
USC-54 USC54
USC-54 USC54
USC-54 USC54
USC-54 USC54
USC-54 USC54
USC-54 USC54
USC-55 USC55
USC-55 USC55
USC-56 USC56
USC-56 USC56
USC-57 USC57
USC-57 USC57
USC-57 USC57
USC-57 USC57
USC-59 USC59
USC-59 USC59
USC-59 USC59
USC-59 USC59
AAL-01 AAL1
AAL-01 AAL1
AAL-01 AAL1
AAL-01 AAL1
AAL-01 AAL1
AAL-01 AAL1
AAL-02 AAL2
AAL-02 AAL2
AAL-02 AAL2
AAL-02 AAL2
AAL-02 AAL2
AAL-02 AAL2
AAL-02 AAL2
AAL-02 AAL2
AAL-03 AAL3
AAL-03 AAL3
AAL-04 AAL4
AAL-04 AAL4
AAL-04 AAL4
AAL-04 AAL4
AAL-04 AAL4
AAL-04 AAL4
AAL-04 AAL4
AAL-04 AAL4
AAL-05 AAL5
AAL-05 AAL5
AAL-05 AAL5
AAL-05 AAL5
IDs in VAFS file but not in main
x
patients being removed from VAF analysis due to no follow-up visit
ID Treatment visit_1 Hugo_Symbol cDNA_Change AF_1 Time visit_FU AF_FU
17 Vitamin C Baseline TP53 c.524G>A 0.4836 NA NA NA
17 Vitamin C Baseline CEBPA c.53_65delACCTGCAGAGCCC 0.8424 NA NA NA
17 Vitamin C Baseline RUNX1 c.506_507insG 0.4884 NA NA NA
17 Vitamin C Baseline TET2 c.2594_2595insG 0.4948 NA NA NA
17 Vitamin C Baseline TET2 c.4393C>T 0.475446933695406 NA NA NA
17 Vitamin C Baseline SRSF2 c.284C>T 0.5 NA NA NA
21 Vitamin C Baseline PTPN11 c.794G>A 0.0299 NA NA NA
21 Vitamin C Baseline DNMT3A c.1627G>T 0.206734 NA NA NA
21 Vitamin C Baseline U2AF1 c.470A>G 0.188 NA NA NA
21 Vitamin C Baseline TET2 c.1742delG 0.0437 NA NA NA
21 Vitamin C Baseline TET2 c.3763_3764insA 0.2138 NA NA NA
21 Vitamin C Baseline TET2 c.5083_5084insAT 0.041 NA NA NA
21 Vitamin C Baseline TET2 c.5273_5274insA 0.137 NA NA NA
32 Placebo Baseline SF3B1 c.2098A>G 0.4736 NA NA NA
43 Vitamin C Baseline SF3B1 c.2098A>G 0.465 NA NA NA
48 Vitamin C Baseline U2AF1 c.470A>C 0.07 NA NA NA
48 Vitamin C Baseline ZRSR2 c.935G>T 0.192 NA NA NA
76 Vitamin C Baseline TET2 c.4707C>A 0.451091045899172 NA NA NA
76 Vitamin C Baseline SRSF2 c.284C>G 0.4293 NA NA NA
82 Vitamin C Baseline ASXL1 c.3907A>T 0.351 NA NA NA
87 Placebo Baseline NRAS c.35G>A 0.0218 NA NA NA
87 Placebo Baseline KRAS c.351A>T 0.023 NA NA NA
87 Placebo Baseline U2AF1 c.101C>T 0.479 NA NA NA
87 Placebo Baseline BCOR c.1414G>T 0.988 NA NA NA

Exposure-adjusted incidence rates of adverse and serious adverse events

Code from Stine

## SAE incidence per 100 patient-months:
## Placebo: 11.4
## Vitamin C: 6.6
## 
## AE incidence per 100 patient-months:
## Placebo: 14.2
## Vitamin C: 9.1

Median cumulative Clonal Growth Rates

Bookkeeping

Growth rate, 𝛼 = log (𝑉𝐴𝐹 𝑓𝑜𝑙𝑙𝑜𝑤-𝑢𝑝/𝑉𝐴𝐹 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 )/𝑡𝑖𝑚𝑒 Patients 14 and 96 have no VAF info because they did not have nay VAFS, they are not included in this current version. The below table is all variants, patients can have multiple VAFs.

Placebo
(N=158)		 Vitamin C
(N=173)		 Overall
(N=331)
GR
Mean (SD) 0.272 (1.21) 0.127 (0.988) 0.197 (1.10)
Median [Min, Max] 0.0569 [-2.77, 7.20] 0.0176 [-1.65, 9.90] 0.0404 [-2.77, 9.90]

Median GR

All patients

Primary outcome

Placebo
(N=51)		 Vitamin C
(N=47)		 Overall
(N=98)
GR
Mean (SD) 0.10 (0.22) 0.01 (0.34) 0.06 (0.29)
Median (Q1, Q3) 0.05 (-0.01, 0.22) 0.03 (-0.07, 0.16) 0.04 (-0.03, 0.17)
emmeans and contrast
Treatment emmean SE df lower.CL upper.CL
Placebo 0.0459699 0.0284486 96 -0.0105001 0.1024399
Vitamin C 0.0302582 0.0286091 96 -0.0265304 0.0870469
contrast estimate SE df lower.CL upper.CL
Placebo - Vitamin C 0.0157117 0.040346 96 -0.0643746 0.0957979
p-value on difference
model term df1 df2 F.ratio p.value
Treatment 1 96 0.152 0.6978257

Subgroups

Bookkeeping

Counts per diagnosis main file
Var1 Freq
CCUS 37
CMML_MDS_MPN 28
MDS 41
Patients with baseline TET2, IDH1, or IDH2 mutations
Var1 Freq
CCUS 36
MDS 38
MDS/MPN 23
ID Time Hugo_Symbol
1 1 KRAS
1 1 TET2
1 1 TET2
10 1 SH2B3
10 1 SRSF2
10 1 IDH1
102 1 TET2
104 1 PTPN11
104 1 TET2
104 1 TET2
104 1 TET2
104 1 TET2
104 1 SRSF2
105 1 TET2
105 1 TET2
105 1 ZRSR2
105 1 PHF6
105 1 SRSF2
106 1 CBL
106 1 TET2
106 1 TET2
106 1 SRSF2
11 1 TET2
12 1 KRAS
12 1 SRSF2
12 1 RUNX1
12 1 KIT
12 1 TET2
13 1 TET2
13 1 TET2
13 1 TET2
13 1 TET2
13 1 TET2
13 1 ZRSR2
17 1 TP53
17 1 CEBPA
17 1 RUNX1
17 1 TET2
17 1 TET2
17 1 SRSF2
18 1 DNMT3A
18 1 TET2
19 1 TET2
19 1 TET2
19 1 ZRSR2
20 1 TET2
20 1 TET2
21 1 PTPN11
21 1 DNMT3A
21 1 U2AF1
21 1 TET2
21 1 TET2
21 1 TET2
21 1 TET2
22 1 DNMT3A
22 1 ASXL1
22 1 U2AF1
22 1 TET2
22 1 TET2
22 1 TET2
23 1 DNMT3A
23 1 IDH1
24 1 TET2
24 1 TET2
25 1 TET2
25 1 TET2
25 1 TET2
25 1 SRSF2
26 1 MPL
26 1 SH2B3
26 1 SH2B3
26 1 TET2
26 1 TET2
26 1 JAK2
28 1 DNMT3A
28 1 TET2
3 1 TET2
3 1 TET2
30 1 NF1
30 1 DNMT3A
30 1 RUNX1
30 1 RUNX1
30 1 TET2
30 1 TET2
30 1 BCOR
30 1 STAG2
30 1 SRSF2
31 1 SH2B3
31 1 TP53
31 1 TET2
31 1 ZRSR2
31 1 STAG2
31 1 SRSF2
33 1 TET2
36 1 TET2
36 1 TET2
36 1 NF1
36 1 SRSF2
41 1 IDH2
41 1 DNMT3A
41 1 DNMT3A
41 1 DNMT3A
41 1 TET2
42 1 TET2
46 1 IDH2
46 1 SRSF2
47 1 TET2
47 1 TET2
47 1 ZRSR2
47 1 ZRSR2
50 1 TET2
50 1 SRSF2
51 1 DNMT3A
51 1 TET2
51 1 TET2
51 1 TET2
6 1 DNMT3A
6 1 SF3B1
6 1 SF3B1
6 1 TET2
64 1 TP53
64 1 U2AF1
64 1 TET2
64 1 TET2
66 1 SF3B1
66 1 TET2
66 1 TET2
66 1 ZRSR2
67 1 PTPN11
67 1 RUNX1
67 1 TET2
67 1 TET2
67 1 TET2
67 1 SRSF2
69 1 ASXL1
69 1 ASXL1
69 1 TET2
69 1 TET2
69 1 EZH2
69 1 ZRSR2
69 1 ZRSR2
69 1 ZRSR2
70 1 PPM1D
70 1 TET2
70 1 TET2
70 1 TET2
71 1 TET2
71 1 TET2
71 1 TET2
71 1 TET2
71 1 SRSF2
73 1 KRAS
73 1 ASXL1
73 1 RUNX1
73 1 TET2
73 1 TET2
73 1 SRSF2
74 1 TET2
74 1 TET2
74 1 ZRSR2
75 1 DNMT3A
75 1 TET2
76 1 TET2
76 1 SRSF2
78 1 CBL
78 1 ASXL1
78 1 RUNX1
78 1 TET2
78 1 TET2
78 1 STAG2
8 1 CBL
8 1 CBL
8 1 CBL
8 1 ASXL1
8 1 U2AF1
8 1 TET2
8 1 TET2
8 1 BRAF
80 1 TET2
80 1 TET2
80 1 SRSF2
84 1 RUNX1
84 1 TET2
84 1 SRSF2
88 1 SF3B1
88 1 TET2
88 1 EZH2
89 1 ASXL1
89 1 TET2
89 1 TET2
89 1 ZRSR2
9 1 SH2B3
9 1 RUNX1
9 1 TET2
9 1 TET2
9 1 SRSF2
91 1 TET2
91 1 TET2
91 1 ZRSR2
92 1 SF3B1
92 1 TET2
93 1 IDH1
93 1 ZRSR2
93 1 ZRSR2
93 1 SRSF2
94 1 TET2
94 1 SRSF2
95 1 GNB1
95 1 DNMT3A
95 1 TET2
97 1 KRAS
97 1 ASXL1
97 1 TET2
98 1 MPL
98 1 TET2
98 1 TET2
AAL1 1 SRSF2
AAL1 1 IDH1
AAL1 1 RUNX1
AAL2 1 DNMT3A
AAL2 1 SF3B1
AAL2 1 ASXL1
AAL2 1 TET2
AAL4 1 TET2
AAL4 1 TET2
AAL4 1 ZRSR2
AAL4 1 ZRSR2
AAL5 1 SF3B1
AAL5 1 TET2
USC52 1 SF3B1
USC52 1 TET2
USC52 1 STAG2
USC53 1 TET2
USC53 1 TET2
USC53 1 TET2
USC53 1 TET2
USC53 1 ZRSR2
USC53 1 SRSF2
USC57 1 TET2
USC57 1 TET2

TET2 mutation status

Median baseline vitamin C mutation status

Baseline diagnosis

Individual mutations

Counts of each mutation
Var1 Freq
FLT3 1
GNB1 1
NRAS 1
PHF6 1
PPM1D 1
SETBP1 1
BCOR 2
BRAF 2
ETNK1 2
ETV6 2
GATA2 2
JAK2 2
KIT 2
MPL 2
CEBPA 3
EZH2 3
IDH2 3
NF1 3
PTPN11 3
IDH1 4
CBL 6
KRAS 6
SH2B3 6
STAG2 7
TP53 7
U2AF1 7
RUNX1 14
SF3B1 21
ASXL1 24
ZRSR2 26
SRSF2 27
DNMT3A 31
TET2 108

Plasma Vitamin C

Manuscript Figure

Patient plasma vitamin C level. A) Composition of all patients, placebo controls, and vitamin C treated individuals with: vitamin C deficiency, inadequate vitamin C, or adequate vitamin C at inclusion; distributions are relatively similar between the two treatment arms. B) Plasma vitamin C level at each timepoint by treatment arm; p-values were estimated using robust linear mixed-effects model with a random intercept for each individual. C) LOESS smoothed vitamin C level over time with standard error ribbons. Individuals with >200 /L vitamin C level were censored in C) to better characterize dispersion among trial participants, all individual measures are shown in panel B).

Supplemental figure, Vitamin C change over time

Supplemental figure xx. Change in vitamin C over time.

Placebo
(N=54)		 Vitamin C
(N=55)		 Overall
(N=109)
Baseline Vitamin C
Mean (SD) 43.66 (24.55) 47.64 (25.17) 45.67 (24.83)
Median (Q1, Q3) 43.75 (22.20, 60.39) 45.85 (29.80, 69.12) 44.18 (27.33, 63.32)
EOT Vitamin C
Mean (SD) 45.31 (31.09) 83.22 (24.40) 65.12 (33.56)
Median (Q1, Q3) 48.73 (20.56, 58.21) 81.90 (67.08, 99.57) 63.82 (47.69, 87.34)
Missing 12 (22.2%) 9 (16.4%) 21 (19.3%)
change in vitamin C
Treatment_arm emmean SE df z.ratio p.value
Placebo -0.7534369 4.882218 NA -0.1543227 0.8773553
Vitamin C 36.8381243 4.665120 NA 7.8965003 0.0000000
Fold change in vitamin C
Treatment_arm response SE df asymp.LCL asymp.UCL
Placebo 0.9257738 0.0960257 NA 0.7554647 1.134477
Vitamin C 1.9340593 0.1916894 NA 1.5925941 2.348737
contrast ratio SE df asymp.LCL asymp.UCL
Placebo / Vitamin C 0.4786688 0.0686721 NA 0.3613414 0.6340922

Supplemental figure, plasma versus bone marrow vitamin C

Correlate Vitamin C in plasma and bone marrow

Spearman

Survival

Includes all samples, unadjusted. We also performed a landmark analysis and analyzed this same data with peto-peto. Both were still significant, therefore an FDR correction would not change our findings here.

Primary outcome KM (Figure 3)

Unadjusted Kaplan-Meier curves for overall survival. Estimated hazard ratio for vitamin C treated patients versus controls based on an unadjusted Cox proportional hazards regression 0.35, 95% CI 0.17, 0.71.

Placebo
(N=54)		 Vitamin C
(N=55)		 Overall
(N=109)
Follow up (Months)
Mean (sd) 30.6 (17.0) 39.3 (17.8) 35.0 (17.9)
Median [Q1, Q3] 28.1 [18.2, 41.2] 36.4 [25.8, 49.5] 33.6 [21.4, 48.3]
Event
Censored 30 (55.6%) 44 (80.0%) 74 (67.9%)
Died 24 (44.4%) 11 (20.0%) 35 (32.1%)

Hazard ratio and CI
exp(coef) exp(-coef) lower .95 upper .95
Treatment_armVitamin C 0.3473816 2.878679 0.1697418 0.7109265

Cox model (No interaction)

Supplemntal figure XX. Forest plot for adjusted Cox model. Cox proportional hazards regression to estimated efficacy of vitamin C on overall survival was adjusted for patient age at inclusion, gender, hemoglobin levels at inclusion, and whether or not they had been diagnosed with CCUS.

Cox model (Age interaction)

Supplemental figure XX. Forest plot for adjusted Cox model in age interaction. Cox proportional hazards regression to estimated efficacy of vitamin C as a function of age. Age was mean centered and converted to decades to improve hazard ratio scales. Overall vitamin C was still effective, with evidence that it’s efficacy decreases with age.

Cox model (TET interaction)

Placebo Vitamin C
TET2Mut 32 31
TET2neg 22 24

Cox model (Hb1 interaction)

Cox model (Sex interaction)

Cox model (CCUS interaction)

Forest plot cannot be made due to diverging SE in treatment

## Call:
## coxph(formula = Surv(Days_FU_OS, FU_Death) ~ VitaminC + age_c + 
##     vitc_ccus + Male + Hb1_c + CCUS, data = df)
## 
##                       coef        exp(coef)         se(coef)      z        p
## VitaminC    -0.48013788583    0.61869807622    0.39738120115 -1.208 0.226949
## age_c        0.04289957950    1.04383306735    0.02439246075  1.759 0.078625
## vitc_ccus  -18.85453900918    0.00000000648 5424.03021304527 -0.003 0.997226
## Male         0.84285200671    2.32298270049    0.46551028687  1.811 0.070203
## Hb1_c       -0.67791720098    0.50767327337    0.18565236465 -3.652 0.000261
## CCUS         0.23284559292    1.26218657373    0.51029109759  0.456 0.648175
## 
## Likelihood ratio test=40.98  on 6 df, p=0.0000002919
## n= 109, number of events= 35

Cox model (baseline vitamin C interaction)

2-year landmark

Maybe Figure? A 2 year landmark analysis was performed to determine if there was still evidence of vitamin C efficacy after removing individuals who had events prior to 2 years. This landmark analysis ensures the effects of vitamin C had sufficient time to reach efficacy.

Removed from landmark
ID Days_FU_OS FU_Death Treatment_arm
9 531 1 Vitamin C
12 403 1 Placebo
17 113 1 Vitamin C
23 360 1 Placebo
27 606 1 Vitamin C
30 621 1 Vitamin C
33 646 1 Placebo
35 683 1 Placebo
37 379 1 Placebo
42 618 1 Placebo
44 132 1 Placebo
65 235 1 Placebo
73 413 1 Placebo
78 479 1 Placebo
81 250 1 Placebo
83 578 1 Vitamin C
87 391 1 Placebo
95 701 0 Placebo
96 666 0 Vitamin C
97 658 0 Placebo
98 650 0 Vitamin C
99 650 0 Vitamin C
100 608 0 Vitamin C
101 594 0 Placebo
102 539 0 Placebo
103 152 1 Vitamin C
104 462 0 Vitamin C
105 401 0 Vitamin C
106 364 0 Placebo
AAL2 509 1 Placebo
AAL5 386 0 Placebo
USC53 695 1 Placebo
USC59 714 0 Placebo
USC60 1 0 Placebo

Per patient protocol

likelihood ratio test p-value is nearly identical to log-rank

IDs removed from main
x
1
12
17
21
23
30
32
33
35
37
43
44
48
65
72
74
76
78
81
82
87
96
103
AAL2
AAL4

LRT on treatment
#Df LogLik Df Chisq Pr(>Chisq)
1 -76.00080 NA NA NA
0 -77.16977 -1 2.337937 0.1262567

Subgroups (suppl)

All subgroup analyses include only the hazard ratio with 95% CI as these are exploratory.

TET1 or IDH1/2 at baseline

Supplemental Figure XX. Overall survival by TET2 or IDH1/2 mutation status. Hazard ratio and confidence intervals were estimated using Cox proportional hazards models on data stratified by TET2 and IDH1/2 mutation status. Survival curves and estimates are consistent with the primary outcome.

LRT for interaction
#Df LogLik Df Chisq Pr(>Chisq)
3 -142.8280 NA NA NA
2 -143.5895 -1 1.523109 0.2171495

Manuscript Figure

LOF TET2

AKA TET2 hypermethylation vs WT signature

LRT for interaction
#Df LogLik Df Chisq Pr(>Chisq)
3 -107.0926 NA NA NA
2 -107.8713 -1 1.557548 0.2120246

Above/Below median Vitamin C

Supplemental figure XX. Overall survival by vitamin C above or below median vitamin C at inclusion. Hazard ratio and confidence intervals were estimated using Cox proportional hazards models on data stratified by patients with plasma vitamin C level below the median measure at inclusion, and greater than or equal to the median. Results are consistent with the primary outcome.

LRT for interaction
#Df LogLik Df Chisq Pr(>Chisq)
3 -142.7831 NA NA NA
2 -142.7974 -1 0.0284974 0.8659447

Diagnostic subgroup

Supplemental figure XX. Overall survival by diagnostic subgroup at inclusion. Hazard ratio and confidence intervals were estimated using Cox proportional hazards models on data stratified by diagnosis at inclusion. CCUS appears to be a subgroup that can benefit particularly well from vitamin C supplementation.

LRT for interaction
#Df LogLik Df Chisq Pr(>Chisq)
11 -134.4270 NA NA NA
6 -138.5647 -5 8.275447 0.1416943

Competing risk regression (progression)

For this analysis death is a competing risk of high-risk progression. We are a bit limited in sample size and events; there are only 14 progression events. Power to detect any differences in progression is quite low and we will have difficulty adjusting for any covariates here. We see corroboration with our overall survival findings that death (the dotted lines) are significantly different, however we do not have enough evidence to determine if progression also differs.

Global Methylation

Figure XX. Global methylation changes over time by treatment arm A) 5-mC/dG and B) 5-hmC/5-mC level for each patient at inclusion and end-of-therapy (EOT) and the change in these measures between inclusion and EOT. Data were analyzed using robust linear mixed-effects models with a random intercept for each patient and an interaction between treatment and time point to assess if measures changed differently over time. Models also included a covariate for batch.

Methylation IDs not in Mass Spec data
x
75
79
6
5
4
26
47
23
93

Delta 5-mC and 5-hmC/5-mC

TET2

baseline vitamin C

Diagnosis

Baseline 5-mC and 5-hmC/5-mC

The raw p-values should be printing in each section

Saved p-values and FDR adjustments
outcome subgroup p FDR
mC.dG TET2 0.1991000 0.2844286
mC.dG vitc_med 0.1066000 0.2132000
mC.dG vitc_ccus 0.0078000 0.0390000
mC.dG vitc_ccus 0.6186000 0.6873333
mC.dG vitc_ccus 0.0797000 0.2092500
hmC.mC TET2 0.0000001 0.0000009
hmC.mC vitc_med 0.5790000 0.6873333
hmC.mC vitc_ccus 0.7838000 0.7838000
hmC.mC vitc_ccus 0.1405000 0.2341667
hmC.mC vitc_ccus 0.0837000 0.2092500

TET2

baseline vitamin C

Diagnosis

5-mC/dG

All corr

##            
##             All
##   Placebo    45
##   Vitamin C  40

TET2

##            
##             No TET2 or IDH1/2 mutation TET2 or IDH1/2 mutation
##   Placebo                           16                      29
##   Vitamin C                         18                      22

LOF TET2

##            
##             TET2 WT signature TET2 hypermethylation signature
##   Placebo                  25                              15
##   Vitamin C                21                              14

Median Vitamin C

##            
##             Below median Above median
##   Placebo             23           22
##   Vitamin C           19           21

Vitamin C Severe

##            
##             Severe (< 11.4 μmol/L) All others
##   Placebo                        4         41
##   Vitamin C                      2         38

Diagnosis (CCUS)

##            
##             CCUS MDS MDS/MPN
##   Placebo     16  17      11
##   Vitamin C   15  17       7

5-hmC/dG

All corr

##            
##             All
##   Placebo    45
##   Vitamin C  40

TET2

##            
##             No TET2 or IDH1/2 mutation TET2 or IDH1/2 mutation
##   Placebo                           16                      29
##   Vitamin C                         18                      22

LOF TET2

##            
##             TET2 WT signature TET2 hypermethylation signature
##   Placebo                  25                              15
##   Vitamin C                21                              14

Median Vitamin C

##            
##             Below median Above median
##   Placebo             23           22
##   Vitamin C           19           21

Vitamin C Severe

##            
##             Severe (< 11.4 μmol/L) All others
##   Placebo                        4         41
##   Vitamin C                      2         38

Diagnosis (CCUS)

##            
##             CCUS MDS MDS/MPN
##   Placebo     16  17      11
##   Vitamin C   15  17       7

5-hmC/5-mC

All corr

##            
##             All
##   Placebo    45
##   Vitamin C  40

TET2

##            
##             No TET2 or IDH1/2 mutation TET2 or IDH1/2 mutation
##   Placebo                           16                      29
##   Vitamin C                         18                      22

LOF TET2

##            
##             TET2 WT signature TET2 hypermethylation signature
##   Placebo                  25                              15
##   Vitamin C                21                              14

Median Vitamin C

##            
##             Below median Above median
##   Placebo             23           22
##   Vitamin C           19           21

Vitamin C Severe

##            
##             Severe (< 11.4 μmol/L) All others
##   Placebo                        4         41
##   Vitamin C                      2         38

Diagnosis (CCUS)

##            
##             CCUS MDS MDS/MPN
##   Placebo     16  17      11
##   Vitamin C   15  17       7

Manuscript Figure

rlmer estimates 5mC/dG
Estimate Std. Error t value 2.5% 97.5%
(Intercept) 0.0352878 0.0010852 32.5174893 0.0331609 0.0374147
Treatment_armVitamin C 0.0004736 0.0007077 0.6692364 -0.0009135 0.0018608
TimepointEOT -0.0000521 0.0003274 -0.1590705 -0.0006938 0.0005896
Batch 0.0009001 0.0006899 1.3047354 -0.0004520 0.0022523
Treatment_armVitamin C:TimepointEOT -0.0004371 0.0004760 -0.9183844 -0.0013700 0.0004957
Time comparisons by treatment 5mC/dG
Timepoint Treatment_arm emmean SE df asymp.LCL asymp.UCL
Baseline Placebo 0.0366380 0.0005055 Inf 0.0356473 0.0376287
EOT Placebo 0.0365859 0.0005122 Inf 0.0355819 0.0375899
Baseline Vitamin C 0.0371116 0.0005036 Inf 0.0361245 0.0380987
EOT Vitamin C 0.0366224 0.0005234 Inf 0.0355966 0.0376483
contrast Treatment_arm estimate SE df z.ratio p.value
Baseline - EOT Placebo 0.0000521 0.0003274 Inf 0.1590705 0.8736133
Baseline - EOT Vitamin C 0.0004892 0.0003457 Inf 1.4149172 0.1570928
anova on 5mC/dG model
model term df1 df2 F.ratio Chisq p.value
1 Treatment_arm 1 Inf 0.143 0.143 0.7057041
3 Timepoint 1 Inf 1.291 1.291 0.2558292
4 Batch 1 Inf 1.702 1.702 0.1919830
2 Treatment_arm:Timepoint 1 Inf 0.843 0.843 0.3584176
Baseline
EOT
Overall
Placebo
(N=48)		 Vitamin C
(N=48)		 Placebo
(N=45)		 Vitamin C
(N=40)		 Placebo
(N=93)		 Vitamin C
(N=88)
mC.dG
Mean (SD) 0.04 (0.00) 0.04 (0.00) 0.04 (0.00) 0.04 (0.00) 0.04 (0.00) 0.04 (0.00)
Median (Q1, Q3) 0.04 (0.03, 0.04) 0.04 (0.03, 0.04) 0.04 (0.03, 0.04) 0.04 (0.03, 0.04) 0.04 (0.03, 0.04) 0.04 (0.03, 0.04)
rlmer estimates 5hmC/5mC
Estimate Std. Error t value 2.5% 97.5%
(Intercept) 0.0067577 0.0008970 7.5339083 0.0049996 0.0085157
Treatment_armVitamin C -0.0002895 0.0005735 -0.5047597 -0.0014134 0.0008345
TimepointEOT -0.0001792 0.0001756 -1.0205230 -0.0005234 0.0001650
Batch 0.0002108 0.0005732 0.3677627 -0.0009127 0.0013343
Treatment_armVitamin C:TimepointEOT -0.0000737 0.0002557 -0.2884575 -0.0005748 0.0004274
Time comparisons by treatment 5hmC/5mC
Timepoint Treatment_arm emmean SE df asymp.LCL asymp.UCL
Baseline Placebo 0.0070739 0.0004098 Inf 0.0062707 0.0078770
EOT Placebo 0.0068947 0.0004123 Inf 0.0060865 0.0077028
Baseline Vitamin C 0.0067844 0.0004082 Inf 0.0059843 0.0075845
EOT Vitamin C 0.0065315 0.0004157 Inf 0.0057168 0.0073461
contrast Treatment_arm estimate SE df z.ratio p.value
Baseline - EOT Placebo 0.0001792 0.0001756 Inf 1.020523 0.3074805
Baseline - EOT Vitamin C 0.0002529 0.0001859 Inf 1.360685 0.1736134
anova on 5hmC/5mC model
model term df1 df2 F.ratio Chisq p.value
1 Treatment_arm 1 Inf 0.337 0.337 0.5616665
3 Timepoint 1 Inf 2.855 2.855 0.0910993
4 Batch 1 Inf 0.135 0.135 0.7130502
2 Treatment_arm:Timepoint 1 Inf 0.083 0.083 0.7729965
Baseline
EOT
Overall
Placebo
(N=48)		 Vitamin C
(N=48)		 Placebo
(N=45)		 Vitamin C
(N=40)		 Placebo
(N=93)		 Vitamin C
(N=88)
hmC.mC
Mean (SD) 0.01 (0.00) 0.01 (0.00) 0.01 (0.00) 0.01 (0.00) 0.01 (0.00) 0.01 (0.00)
Median (Q1, Q3) 0.01 (0.01, 0.01) 0.01 (0.00, 0.01) 0.01 (0.00, 0.01) 0.01 (0.00, 0.01) 0.01 (0.01, 0.01) 0.01 (0.00, 0.01)

Cytokines

Primary Analysis, all patients

Suppl all cytokines

Supplemental Figure XX. log2 fold-change in cytokine measures for all individuals. Data were analyzed using robust linear mixed-effects models with a random intercept for each patient and an interaction between treatment and timepoint to assess if measures changed differently over time.

##        assay              p         est         se     lower.CL    upper.CL
## 1      G-CSF 0.000000993444  0.36203915 0.07399226  0.217016985  0.50706132
## 2      M-CSF 0.000013368291  0.20350913 0.04674086  0.111898739  0.29511952
## 3     SDF-1α 0.068275092101  0.07780182 0.04267353 -0.005836762  0.16144040
## 4    IL-8_HA 0.921056676560  0.02158438 0.21779796 -0.405291770  0.44846053
## 5      IP-10 0.000851818408  0.22846630 0.06849776  0.094213157  0.36271945
## 6     GM-CSF 0.279815112669  0.24789754 0.22937871 -0.201676461  0.69747155
## 7      IL-1α 0.068238361571 -0.48547808 0.26624450 -1.007307704  0.03635155
## 8       IL-7 0.918663490278  0.00724773 0.07097448 -0.131859702  0.14635516
## 9  VEGF_cyto 0.606548513319  0.03241339 0.06293783 -0.090942496  0.15576928
## 10     IFN-γ 0.092585139131  0.22090012 0.13133839 -0.036518380  0.47831863
## 11     IL-10 0.000235517838  0.37304687 0.10143995  0.174228223  0.57186552
## 12  IL-12p70 0.246938199335  0.12563311 0.10850849 -0.087039615  0.33830583
## 13     IL-17 0.150309934553  0.19052021 0.13244941 -0.069075863  0.45011628
## 14     IL-1β 0.731113881036 -0.09466604 0.27547690 -0.634590846  0.44525877
## 15      IL-4 0.477320703966  0.18136156 0.25521651 -0.318853609  0.68157674
## 16      IL-6 0.000033671522  0.48882204 0.11787085  0.257799415  0.71984467
## 17     TNF-α 0.029346921512  0.18606825 0.08539962  0.018688062  0.35344844
## 18    RANTES 0.007350354898 -0.36581992 0.13647249 -0.633301076 -0.09833876
## 19    TGF-β1 0.025886779832 -0.13584708 0.06097523 -0.255356340 -0.01633783
Significant changes over time by treatment
assay contrast Treatment_arm estimate SE df z.ratio p.value FDR FoldChange
G-CSF Baseline - EOT Placebo -0.1743696 0.0519787 Inf -3.3546344 0.0007947 0.0037748 1.1284712
G-CSF Baseline - EOT Vitamin C 0.1876696 0.0526599 Inf 3.5638023 0.0003655 0.0019843 0.8780229
M-CSF Baseline - EOT Placebo -0.2528030 0.0328338 Inf -7.6994741 0.0000000 0.0000000 1.1915198
M-CSF Baseline - EOT Vitamin C -0.0492938 0.0332663 Inf -1.4817929 0.1383954 0.3578402 1.0347583
SDF-1α Baseline - EOT Placebo -0.1117457 0.0299780 Inf -3.7275946 0.0001933 0.0012243 1.0805349
SDF-1α Baseline - EOT Vitamin C -0.0339439 0.0303702 Inf -1.1176700 0.2637080 0.5203999 1.0238071
IL-8_HA Baseline - EOT Placebo 0.0042498 0.1529807 Inf 0.0277798 0.9778378 0.9778378 0.9970586
IL-8_HA Baseline - EOT Vitamin C 0.0258342 0.1550253 Inf 0.1666448 0.8676496 0.9158523 0.9822525
IP-10 Baseline - EOT Placebo -0.2087999 0.0477696 Inf -4.3709833 0.0000124 0.0001567 1.1557264
IP-10 Baseline - EOT Vitamin C 0.0196664 0.0490919 Inf 0.4006031 0.6887124 0.7697374 0.9864608
GM-CSF Baseline - EOT Placebo -0.1400681 0.1612918 Inf -0.8684141 0.3851677 0.5854549 1.1019571
GM-CSF Baseline - EOT Vitamin C 0.1078295 0.1630937 Inf 0.6611506 0.5085157 0.6475787 0.9279832
IL-1α Baseline - EOT Placebo 0.1326469 0.1872146 Inf 0.7085283 0.4786173 0.6475787 0.9121564
IL-1α Baseline - EOT Vitamin C -0.3528312 0.1893061 Inf -1.8638129 0.0623480 0.1875775 1.2770643
IL-7 Baseline - EOT Placebo -0.0437187 0.0496925 Inf -0.8797848 0.3789759 0.5854549 1.0307674
IL-7 Baseline - EOT Vitamin C -0.0364710 0.0506757 Inf -0.7196941 0.4717134 0.6475787 1.0256020
VEGF_cyto Baseline - EOT Placebo -0.0815753 0.0440712 Inf -1.8509883 0.0641712 0.1875775 1.0581729
VEGF_cyto Baseline - EOT Vitamin C -0.0491619 0.0449321 Inf -1.0941374 0.2738947 0.5203999 1.0346637
IFN-γ Baseline - EOT Placebo -0.0916601 0.0916500 Inf -1.0001106 0.3172570 0.5740841 1.0655956
IFN-γ Baseline - EOT Vitamin C 0.1292400 0.0940747 Inf 1.3738017 0.1695033 0.3578402 0.9143130
IL-10 Baseline - EOT Placebo -0.2665197 0.0707810 Inf -3.7654125 0.0001663 0.0012243 1.2029025
IL-10 Baseline - EOT Vitamin C 0.1065271 0.0726644 Inf 1.4660161 0.1426439 0.3578402 0.9288212
IL-12p70 Baseline - EOT Placebo 0.0666808 0.0757469 Inf 0.8803108 0.3786910 0.5854549 0.9548323
IL-12p70 Baseline - EOT Vitamin C 0.1923139 0.0776949 Inf 2.4752432 0.0133145 0.0505953 0.8752009
IL-17 Baseline - EOT Placebo -0.1301076 0.0924251 Inf -1.4077087 0.1592173 0.3578402 1.0943753
IL-17 Baseline - EOT Vitamin C 0.0604126 0.0948707 Inf 0.6367888 0.5242624 0.6475787 0.9589898
IL-1β Baseline - EOT Placebo -0.0080323 0.1924598 Inf -0.0417348 0.9667101 0.9778378 1.0055831
IL-1β Baseline - EOT Vitamin C -0.1026983 0.1970958 Inf -0.5210578 0.6023265 0.6935881 1.0737799
IL-4 Baseline - EOT Placebo -0.2480545 0.1781690 Inf -1.3922428 0.1638489 0.3578402 1.1876045
IL-4 Baseline - EOT Vitamin C -0.0666929 0.1827328 Inf -0.3649749 0.7151301 0.7764270 1.0473132
IL-6 Baseline - EOT Placebo -0.4355809 0.0822540 Inf -5.2955589 0.0000001 0.0000023 1.3524553
IL-6 Baseline - EOT Vitamin C 0.0532411 0.0844264 Inf 0.6306218 0.5282879 0.6475787 0.9637687
TNF-α Baseline - EOT Placebo -0.1323477 0.0595905 Inf -2.2209543 0.0263541 0.0910413 1.0960759
TNF-α Baseline - EOT Vitamin C 0.0537205 0.0611725 Inf 0.8781813 0.3798453 0.5854549 0.9634485
RANTES Baseline - EOT Placebo 0.0555723 0.0952164 Inf 0.5836425 0.5594608 0.6643597 0.9622127
RANTES Baseline - EOT Vitamin C -0.3102476 0.0977680 Inf -3.1733040 0.0015071 0.0063635 1.2399205
TGF-β1 Baseline - EOT Placebo -0.0286679 0.0425698 Inf -0.6734335 0.5006716 0.6475787 1.0200698
TGF-β1 Baseline - EOT Vitamin C -0.1645150 0.0436554 Inf -3.7684954 0.0001642 0.0012243 1.1207892
Cytokines that changed differently over time for Placebo versus Vitamin C
assay p est se lower.CL upper.CL FDR
1 G-CSF 0.0000010 0.3620392 0.0739923 0.2170170 0.5070613 0.0000189
2 M-CSF 0.0000134 0.2035091 0.0467409 0.1118987 0.2951195 0.0001270
5 IP-10 0.0008518 0.2284663 0.0684978 0.0942132 0.3627194 0.0032369
11 IL-10 0.0002355 0.3730469 0.1014400 0.1742282 0.5718655 0.0011187
16 IL-6 0.0000337 0.4888220 0.1178709 0.2577994 0.7198447 0.0002133
18 RANTES 0.0073504 -0.3658199 0.1364725 -0.6333011 -0.0983388 0.0232761

Cytokine figure

Supplemental Figure XX. log2 fold-change in cytokine measures that changed significantly. Data were analyzed using robust linear mixed-effects models with a random intercept for each patient and an interaction between treatment and timepoint to assess if measures changed differently over time. Larger points indicate the mean log2(fold-change) with 95% CI error bars. Scales were limited to +/-1.5 log2(fold-change) to better characterize dispersion, all data points are shown in supplemental figure XX. P-values were false discovery rate adjusted using Benjamini-Hochberg.

assay Treatment_arm FoldChange FC.CI Median change IQR Q1 Q3
7 IL-6 Placebo 1.3524553 1.21, 1.51 978.7228275 4825.271944 -547.8988763 4277.373068
8 Vitamin C 0.9637687 0.86, 1.08 -305.2321957 2914.539854 -2108.8462637 805.693590
5 IL-10 Placebo 1.2029025 1.09, 1.32 48.3126753 560.975421 -64.9184297 496.056992
6 Vitamin C 0.9288212 0.84, 1.03 -48.4402901 366.301656 -225.0746532 141.227002
1 CXCL10 (IP-10) Placebo 1.1557264 1.08, 1.23 97.4263341 380.265155 -12.0727578 368.192398
2 Vitamin C 0.9864608 0.92, 1.05 -26.4342630 342.846245 -202.3496241 140.496621
9 M-CSF Placebo 1.1915198 1.14, 1.25 1.9633393 3.361131 0.7072681 4.068399
10 Vitamin C 1.0347583 0.99, 1.08 0.4335928 3.483504 -1.5130604 1.970444
3 G-CSF Placebo 1.1284712 1.05, 1.21 0.3595211 7.581336 -1.5821809 5.999155
4 Vitamin C 0.8780229 0.82, 0.94 -0.9363409 5.804647 -4.5238150 1.280832
11 RANTES (CCL5) Placebo 0.9622127 0.85, 1.1 -47.1448291 2897.441686 -1427.1604226 1470.281263
12 Vitamin C 1.2399205 1.09, 1.42 337.3523208 3489.165477 -1355.5910368 2133.574440

Volcano plots of each subroup by assay

Subgroup plots

All subgroups

95% CIs for subgroup comparisons

TET2

Showing only those with FDR < 0.1

## 
## 
## |Var1      |Var2           |Var3                        | Freq|
## |:---------|:--------------|:---------------------------|----:|
## |Placebo   |G-CSF          |No TET2 or IDH1/2 mutations |   22|
## |Vitamin C |G-CSF          |No TET2 or IDH1/2 mutations |   23|
## |Placebo   |IL-10          |No TET2 or IDH1/2 mutations |   22|
## |Vitamin C |IL-10          |No TET2 or IDH1/2 mutations |   23|
## |Placebo   |IL-6           |No TET2 or IDH1/2 mutations |   22|
## |Vitamin C |IL-6           |No TET2 or IDH1/2 mutations |   23|
## |Placebo   |CXCL10 (IP-10) |No TET2 or IDH1/2 mutations |   22|
## |Vitamin C |CXCL10 (IP-10) |No TET2 or IDH1/2 mutations |   23|
## |Placebo   |M-CSF          |No TET2 or IDH1/2 mutations |   22|
## |Vitamin C |M-CSF          |No TET2 or IDH1/2 mutations |   23|
## |Placebo   |TGF-β1         |No TET2 or IDH1/2 mutations |   22|
## |Vitamin C |TGF-β1         |No TET2 or IDH1/2 mutations |   23|
## |Placebo   |TNF-α          |No TET2 or IDH1/2 mutations |   22|
## |Vitamin C |TNF-α          |No TET2 or IDH1/2 mutations |   23|
## |Placebo   |VEGF           |No TET2 or IDH1/2 mutations |   22|
## |Vitamin C |VEGF           |No TET2 or IDH1/2 mutations |   23|
## |Placebo   |G-CSF          |TET2 or IDH1/2 mutation     |   32|
## |Vitamin C |G-CSF          |TET2 or IDH1/2 mutation     |   31|
## |Placebo   |IL-10          |TET2 or IDH1/2 mutation     |   32|
## |Vitamin C |IL-10          |TET2 or IDH1/2 mutation     |   31|
## |Placebo   |IL-6           |TET2 or IDH1/2 mutation     |   32|
## |Vitamin C |IL-6           |TET2 or IDH1/2 mutation     |   31|
## |Placebo   |CXCL10 (IP-10) |TET2 or IDH1/2 mutation     |   32|
## |Vitamin C |CXCL10 (IP-10) |TET2 or IDH1/2 mutation     |   31|
## |Placebo   |M-CSF          |TET2 or IDH1/2 mutation     |   32|
## |Vitamin C |M-CSF          |TET2 or IDH1/2 mutation     |   31|
## |Placebo   |TGF-β1         |TET2 or IDH1/2 mutation     |   32|
## |Vitamin C |TGF-β1         |TET2 or IDH1/2 mutation     |   31|
## |Placebo   |TNF-α          |TET2 or IDH1/2 mutation     |   32|
## |Vitamin C |TNF-α          |TET2 or IDH1/2 mutation     |   31|
## |Placebo   |VEGF           |TET2 or IDH1/2 mutation     |   32|
## |Vitamin C |VEGF           |TET2 or IDH1/2 mutation     |   31|

Median Vitamin C
## 
## 
## |Var1      |Var2           |Var3                   | Freq|
## |:---------|:--------------|:----------------------|----:|
## |Placebo   |G-CSF          |Below median vitamin C |   28|
## |Vitamin C |G-CSF          |Below median vitamin C |   26|
## |Placebo   |IL-10          |Below median vitamin C |   28|
## |Vitamin C |IL-10          |Below median vitamin C |   26|
## |Placebo   |IL-6           |Below median vitamin C |   28|
## |Vitamin C |IL-6           |Below median vitamin C |   26|
## |Placebo   |CXCL10 (IP-10) |Below median vitamin C |   28|
## |Vitamin C |CXCL10 (IP-10) |Below median vitamin C |   26|
## |Placebo   |M-CSF          |Below median vitamin C |   28|
## |Vitamin C |M-CSF          |Below median vitamin C |   26|
## |Placebo   |RANTES (CCL5)  |Below median vitamin C |   28|
## |Vitamin C |RANTES (CCL5)  |Below median vitamin C |   26|
## |Placebo   |TGF-β1         |Below median vitamin C |   28|
## |Vitamin C |TGF-β1         |Below median vitamin C |   26|
## |Placebo   |G-CSF          |Above median vitamin C |   26|
## |Vitamin C |G-CSF          |Above median vitamin C |   28|
## |Placebo   |IL-10          |Above median vitamin C |   26|
## |Vitamin C |IL-10          |Above median vitamin C |   28|
## |Placebo   |IL-6           |Above median vitamin C |   26|
## |Vitamin C |IL-6           |Above median vitamin C |   28|
## |Placebo   |CXCL10 (IP-10) |Above median vitamin C |   26|
## |Vitamin C |CXCL10 (IP-10) |Above median vitamin C |   28|
## |Placebo   |M-CSF          |Above median vitamin C |   26|
## |Vitamin C |M-CSF          |Above median vitamin C |   28|
## |Placebo   |RANTES (CCL5)  |Above median vitamin C |   26|
## |Vitamin C |RANTES (CCL5)  |Above median vitamin C |   28|
## |Placebo   |TGF-β1         |Above median vitamin C |   26|
## |Vitamin C |TGF-β1         |Above median vitamin C |   28|

Diagnosis
## 
## 
## |Var1      |Var2           |Var3    | Freq|
## |:---------|:--------------|:-------|----:|
## |Placebo   |G-CSF          |CCUS    |   17|
## |Vitamin C |G-CSF          |CCUS    |   20|
## |Placebo   |IL-10          |CCUS    |   17|
## |Vitamin C |IL-10          |CCUS    |   20|
## |Placebo   |IL-1α          |CCUS    |   17|
## |Vitamin C |IL-1α          |CCUS    |   20|
## |Placebo   |IL-6           |CCUS    |   17|
## |Vitamin C |IL-6           |CCUS    |   20|
## |Placebo   |CXCL10 (IP-10) |CCUS    |   17|
## |Vitamin C |CXCL10 (IP-10) |CCUS    |   20|
## |Placebo   |M-CSF          |CCUS    |   17|
## |Vitamin C |M-CSF          |CCUS    |   20|
## |Placebo   |SDF-1α         |CCUS    |   17|
## |Vitamin C |SDF-1α         |CCUS    |   20|
## |Placebo   |G-CSF          |MDS     |   22|
## |Vitamin C |G-CSF          |MDS     |   18|
## |Placebo   |IL-10          |MDS     |   22|
## |Vitamin C |IL-10          |MDS     |   18|
## |Placebo   |IL-1α          |MDS     |   22|
## |Vitamin C |IL-1α          |MDS     |   18|
## |Placebo   |IL-6           |MDS     |   22|
## |Vitamin C |IL-6           |MDS     |   18|
## |Placebo   |CXCL10 (IP-10) |MDS     |   22|
## |Vitamin C |CXCL10 (IP-10) |MDS     |   18|
## |Placebo   |M-CSF          |MDS     |   22|
## |Vitamin C |M-CSF          |MDS     |   18|
## |Placebo   |SDF-1α         |MDS     |   22|
## |Vitamin C |SDF-1α         |MDS     |   18|
## |Placebo   |G-CSF          |MDS/MPN |   13|
## |Vitamin C |G-CSF          |MDS/MPN |   15|
## |Placebo   |IL-10          |MDS/MPN |   13|
## |Vitamin C |IL-10          |MDS/MPN |   15|
## |Placebo   |IL-1α          |MDS/MPN |   13|
## |Vitamin C |IL-1α          |MDS/MPN |   15|
## |Placebo   |IL-6           |MDS/MPN |   13|
## |Vitamin C |IL-6           |MDS/MPN |   15|
## |Placebo   |CXCL10 (IP-10) |MDS/MPN |   13|
## |Vitamin C |CXCL10 (IP-10) |MDS/MPN |   15|
## |Placebo   |M-CSF          |MDS/MPN |   13|
## |Vitamin C |M-CSF          |MDS/MPN |   15|
## |Placebo   |SDF-1α         |MDS/MPN |   13|
## |Vitamin C |SDF-1α         |MDS/MPN |   15|

Correlogram